Gene Therapy Moves Toward the Mainstream

When two infants received gene therapy in California last weekend, doctors were making a dramatic attempt to create working immune systems that nature was obligated to provide but didn't.

The newborns inherited a rare fatal immune disorder. They carried two copies of a defective gene for the enzyme adenosine deaminase (ADA) that is crucial for the immune system to fight infections. To correct their condition, doctors extracted from the umbilical cord blood stem cells that give rise to all blood cells, then placed them in a nurturing culture with genetically-altered viruses containing normal ADA genes.

Cells don't recognize genes, so genes can't get inside the cells on their own. They need to slip inside in a Trojan horse. The Trojan horse was the virus, genetically crippled so that it wouldn't harm the human host yet would maintain its ability to sneak inside cells. Tucked inside these viral vessels, the normal ADA genes were expected to enter the stem cells. Afterward, the stem cells (that now, doctors hoped, contained the healthy gene) were injected into the babies.

This is what is known as gene therapy. And gene therapy has come a long way, babies.

The two California infants brought to 114 the number of people who have had genes inserted inside their bodies either as therapy or as "markers" for progression of disease and treatments, according to records kept by the National Institutes of Health. Four years ago last week, the first gene marker was placed in a patient. And only three years ago, the first human received gene therapy.

She was a four-year-old girl who, like the two California infants, was born with defective ADA genes, and, therefore, no immune system. Doctors at NIH made medical history in 1990 by treating her and in 1991 by treating a nine-year-old girl with the same disorder by putting healthy ADA cells into the girls' T-lymphocyte blood cells, which are the white blood cells responsible for immune system protection. But T-lymphocytes do not live forever as do blood stem cells. And so, the treatment has had to be repeated.

The girls' immune systems improved significantly, according to Dr. R. Michael Blaese, chief of the National Cancer Institute's Cellular Immunology Section, who was involved with the girls' early treatment and with the stem cell gene therapy of the infants and the two girls. Although the girls have been going to school and doing well, last year Dr. Blaese told the Recombinant DNA Advisory Committee of NIH and the Food and Drug Administration, which authorizes all gene therapy experiments, that they may have "holes" in their immune system.

And so, while the two infants received most of the media attention last week, the girl initially treated in 1991, who is now 11 years old, also received stem cell gene therapy last week at NIH. This summer, the first girl treated, now six, will get similar treatment in hopes of making her immune protection complete.

Dr. Blaese and many other scientists involved in pioneering gene therapy said in interviews last week that they are very excited and hopeful about its future. "We all think it's going to revolutionize the practice of medicine," Dr. Blaese said.

Various forms of gene therapy are now being tried or are about to be tested on an assortment of diseases, including immunodeficiency disease, cystic fibrosis, melanoma and renal cell cancer.

And researchers predict that gene therapy will eventually be available for diseases from AIDS to cancer to diabetes.

There are signs that gene therapy already is knocking on the door of mainstream medicine. Just last month, the Johns Hopkins Medical Institutions applied for a $1.3 million five-year federal grant to open a gene therapy center. Dr. Frank Oski, chairman of pediatrics, said the center could be opening in six months, if funded.

A number of major medical institutions will likely open gene therapy centers eventually, Dr. Oski said. "It's an idea that everyone is talking about." But, he said, he doesn't think more than one is needed in a major population region.

The Hopkins center would initially treat cystic fibrosis, said Dr. William Guggino, who applied for the NIH grant for the Hopkins center. Initially only a few patients a year could be treated. Hopkins regularly sees 280 patients a year with cystic fibrosis.

The center it would become the hub for gene therapy treatment for many other diseases, he said. The Johns Hopkins School of Medicine "just evaluated itself, and gene therapy is one of the new therapies Hopkins expects to use extensively in the next decade," Dr. Guggino said. He said Hopkins and will proceed with gene therapy for cystic fibrosis, whether or not it receives NIH funds for a gene therapy center.